Cochlear transcript diversity and its role in auditory functions implied by an otoferlin short isoform

Huihui Liu, Hongchao Liu, Longhao Wang, Lei Song, Guixian Jiang, Qing Lu, Tao Yang, Hu Peng, Ruijie Cai, Xingle Zhao, Ting Zhao and Hao Wu ()
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Huihui Liu: Shanghai Jiao Tong University School of Medicine
Hongchao Liu: Shanghai Jiao Tong University School of Medicine
Longhao Wang: Shanghai Jiao Tong University School of Medicine
Lei Song: Shanghai Jiao Tong University School of Medicine
Guixian Jiang: Shanghai Jiao Tong University School of Medicine
Qing Lu: Shanghai Jiao Tong University School of Medicine
Tao Yang: Shanghai Jiao Tong University School of Medicine
Hu Peng: Second Military Medical University
Ruijie Cai: Shanghai Jiao Tong University School of Medicine
Xingle Zhao: Shanghai Jiao Tong University School of Medicine
Ting Zhao: Shanghai Jiao Tong University School of Medicine
Hao Wu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Isoforms of a gene may contribute to diverse biological functions. In the cochlea, the repertoire of alternative isoforms remains unexplored. We integrated single-cell short-read and long-read RNA sequencing techniques and identified 236,012 transcripts, 126,612 of which were unannotated in the GENCODE database. Then we analyzed and verified the unannotated transcripts using RNA-seq, RT-PCR, Sanger sequencing, and MS-based proteomics approaches. To illustrate the importance of identifying spliced isoforms, we investigated otoferlin, a key protein involved in synaptic transmission in inner hair cells (IHCs). Upon deletion of the canonical otoferlin isoform, the identified short isoform is able to support normal hearing thresholds but with reduced sustained exocytosis of IHCs, and further revealed otoferlin functions in endocytic membrane retrieval that was not well-addressed previously. Furthermore, we found that otoferlin isoforms are associated with IHC functions and auditory phenotypes. This work expands our mechanistic understanding of auditory functions at the level of isoform resolution.

Date: 2023
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DOI: 10.1038/s41467-023-38621-3

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